Peter Campochiaro is determined to halt the blindness that strikes everyone with retinitis pigmentosa. To get there, he’s relying on one of the hottest areas of research

By Greg Mone

Peter Campochiaro speeds out of his eighth-floor
laboratory at the Wilmer Eye Institute, hustles
down a flight of stairs into his office and pulls
on a white coat hanging on the back of the door.
Immediately, the mustachioed researcher is transformed
into a physician. It’s a standard makeover
for him. Several times each day, this 54-year-old
Eccles Professor of Ophthalmology and Neuroscience
goes from being a scientist who deciphers blinding
diseases of the retina to a doctor who takes care
of patients with those same diseases.

Campochiaro’s
laboratory work has actually led to some remarkable treatments
for retinal conditions. A decade ago, for instance, his
research group helped determine that the damaging blood-vessel
growth in the retina that causes the age-related
eye disease macular degeneration is promoted by
a certain protein. Until then, there had been little
help for the creeping loss of vision that afflicts
millions of older people. They would simply notice
a loss of sight at the very center of their visual
field. Then, over time, the blind spot would move
outwards, until a massive darkness would cover
all but the extreme periphery of their visual field.
The most familiar faces would become hazes; activities
like reading or watching movies would become impossible.
Now, a clinical trial has demonstrated that blocking
the culprit protein with an antibody fragment called
lucentis stops the abnormal blood-vessel growth.
For the first time, ophthalmologists have a way
to slow macular degeneration.

These days, though, Campochiaro’s chief
nemesis is another affliction—retinitis pigmentosa
or RP—a genetic blinding condition that affects
100,000 people in the United States and which no
drug or surgery can halt. “Having no remedy
for a disease is awfully frustrating,” Campochiaro
says, “when you’re in the business
of trying to make patients better.” And so,
finding a treatment for RP has become his current
quest.

But RP is no simple disease. In fact, it’s
considered a family of diseases. Not only does
its cause vary from patient to patient, different
genes incite its effects in different people. In
all, scientists have identified over 100 genes
involved with RP’s progress. So, although
targeting the genetic roots of RP would probably
halt blindness in certain forms of the disease,
it wouldn’t be a cure-all. But Campochiaro
isn’t trying to attack RP’s genesis.
He’s chosen instead to close in on a particular
downstream effect of this disease—oxidative
stress—a perfectly natural process run amok.

*****

Oxidative stress is an unfortunate byproduct
of an utterly basic phenomenon. As our cells use
oxygen to produce the molecule that gives us energy—adenosine
triphosphate or ATP, the very molecule we require
for breathing—they also give out extra baggage
called reactive oxygen species, or free radicals.
But free radicals can be dangerous because they
cart around an unpaired electron that makes them
highly reactive, driving each to find another molecule
to bond with. The trouble begins when free radicals
choose the wrong partner: molecules like protein,
lipids and DNA that can alter their structure in
critical ways, disrupting their function. The result
is oxidative stress, a condition, it turns out,
that can wreak untold havoc on the human body.

Every one of us, of course, encounters oxidative
stress in the course of our lives, and usually
it doesn’t cause problems. The cell’s
self-defense and self-destruct mechanisms simply
work together like sponges to soak up the free
radicals before they attack critical molecules
that can’t be spared. So proficient, in fact,
is our natural defense system that even when free
radicals do manage to slip through—latching
onto proteins, lipids or even going after DNA—the
cell intuits that something fishy is going on:
Enough free radicals have clung to enough proteins,
its instincts tell it, and it activates its self-destruct
mechanism.

Human bodies, though, don’t always work
perfectly. Scientists now know that many disease
processes actually begin when free radicals swamp
cells’ self-defense mechanisms, causing a
self-destruct response so sweeping that massive
cell death occurs. This phenomenon is particularly
menacing when it occurs in the nervous system,
where dead cells can’t be replaced. Several
neurodegenerative diseases, in fact, stem directly
from this malfunction.

And just like Campochiaro, brain science researchers—intrigued
by the idea that they might arrest diseases like
Parkinson’s and Alzheimer’s by learning
to understand oxidative stress—have been
flocking to this line of study. They’re hoping
to stave off these neurlogical afflictions by identifying
the source of free radicals and then coming up
with a way to either reduce their production or
bolster the cells’ self-defense mechanisms
to handle the increased load. Two years ago, in
fact, a Hopkins team demonstrated that reducing
oxidative stress can slow the accumulation of amyloid
plaques—the very protein deposits believed
to be a major contributor to Alzheimer’s
disease.

Another neuroscientist here, pathologist Lee
Martin, is trying to figure out if oxidative stress
relates to the death of neurons in ALS—Lou
Gehrig’s disease. Do rampant free radicals
in the highly vulnerable motor neurons in the spinal
cord actually kick-start the pathogenesis of ALS?
Or is oxidative stress merely a consequence in
these cells? In other words, are we just looking
at signs of sick neurons or are we looking at the
causes of the disease?”

All the noise in this field, Martin says, is
happening because new technology has made it so
much easier to explore questions that have been
around for a long time. “It allows us to
analyze just how oxidative stress works.” It
was “fluorescent markers,” for instance,
that enabled his team to tally the number of free
radicals in motor neurons. Now, Martin’s
used those markers to identify a free-radical population
boom in mice predisposed to ALS. Oxidative stress,
his lab team has discovered, kicked in before any
effects of the disease even took hold. “It
puts it more in the timeline of an antecedent than
an effect,” he says.

Neurologist Ted Dawson has found that in some
Parkinson’s patients, nitric oxide, a common
free radical, attacks and destroys the function
of the gene parkin. And since this gene normally
acts as a kind of guardian for neurons, Parkinson’s
disease can bombard those neurons when the gene
is shut down. “If you could lower oxidative
stress,” Dawson postulates, “some
of these genes might function better. The neurons
might survive longer.”

*****

Meanwhile, Campochiaro keeps plugging way on
deciphering the role of oxidative stress in retinitis
pigmentosa. Tiny figurines and mementos decorate
the shelves and cabinets in the laboratory where
he toils. Most are gifts from lab colleagues. Adjacent
to his desk, there’s a kind of Wall of Fame
filled with framed photographs of former fellows.
These flow over to surround a large poster, a gift
from his wife titled “Peter’s Laws:
The Creed of the Sociopathic Obsessive Compulsive.”

It’s a surprising label for a shy, mild-mannered
guy like Campochiaro, but the poster’s points,
he admits, are a lot more than jokes. “There’s
a bit of truth in my life to each of those laws,” he
says. His workday, for instance, is pure number
3—“Multiple projects lead to multiple
successes.” On an average day, he runs from
monitoring clinical trials for several potential
new drugs for retinal conditions, to juggling ongoing
basic science studies, to intense sessions with
patients with serious visual problems.

But law number 13—“No simply means
begin at one level higher”—Campochiaro
says, pretty much sums up his entire approach to
doing science. That whole method for thinking through
a research project was hammered into him by the
respected neuroscientist Joseph Coyle, whose picture
also graces his Wall of Fame. Coyle, who left Hopkins
for Harvard in 1991, ran the lab that Campochiaro
worked in as a medical student here.

“A lot of times, the results wouldn’t
be what I expected,” Campochiaro recalls, “and
I’d be upset. “Dr. Coyle would tell
me, ‘Oh, that doesn’t matter. What
counts is what it is. Now we have to explain it.’” Hypotheses
are just tools, Campochiaro learned, and “being
wrong isn’t any big deal.” Often you
learn more by being wrong.

Still, in the case of retinitis pigmentosa, it
turned out to be an unexpected result that led
him to oxidative stress. Several years ago, Campochiaro
had begun to suspect that one of the conditions
of the disease, a thinning out of blood vessels
in the retina, stemmed from an overabundance of
oxygen. To test this idea, he placed mice in an
incubator, flooded it with excess oxygen, then
studied tissue samples of their retinas under a
microscope.

> “There’s
an observation that starts you down
a particular path,” Campochiaro
says, “and
one step just leads to another.”

These tissue samples showed Campochiaro that
his theory had been correct that oxygen was dampening
the behavior of a protein responsible for blood
vessel growth. But the experiment had a more surprising
effect. Campochiaro discovered that the high levels
of oxygen were also killing off the photoreceptors
in the retina, meaning that they must be highly
susceptible to oxidative damage.

Right away, Campochiaro started thinking about
the sequence of events that cause RP: First, genetic
mistakes (mutations) lead to the death of the rods,
the nerve cells that are responsible for vision
in low-light conditions and consume the most oxygen.
Then, in a clearly scripted march toward death,
the cones—the cells that process color, work
in bright light and are responsible for our reading
vision—begin to die. But why those cones
die when they aren’t directly altered by
the mutation that affected the rods has been one
of the central mysteries surrounding RP. Scientists
have proposed several theories through the years,
most involving some sort of toxic reaction triggered
by the death of the rods. But Campochiaro realized
something else might be going on, as he stared
at those tissue samples.

The retina’s light-sensitive photoreceptors,
the ophthalmologist knew, were especially sensitive
to oxidative damage. In normal, healthy eyes, the
rod cells consume huge amounts of oxygen, but as
the rods died off, it stood to reason that oxygen
consumption would go down, ending in an oxygen
surplus. This over-supply would then result in
generation of excess reactive oxygen species. Might
not it be these free radicals, Campochiaro asked
himself, that were attacking the cones and causing
them to press their self-destruct buttons? This
malfunctioning system, he conjectured, could then
be triggering cell death in the vital cones that
allow sight to take place. “I thought, wow,
here’s a situation in which oxidative damage
may be leading to the death of cones.”

If his theory were right, it would at last offer
one unifying principle within this complex group
of diseases called retinitis pigmentosa. Campochiaro
hadn’t just found a tidy hypothesis explaining
the death of the cone cells. This idea reached
far beyond simple scientific satisfaction. He now
saw the chance for a treatment for RP where none
had existed before.

*****

Peter Campochiaro is not one for sudden flashes
of inspiration—eureka moments. Rather, his
mind, thoughtfully and methodically, almost never
drifts from his work. (One of Campochiaro’s
research fellows, Katsutoshi Yokoi, mentions that
insightful e-mails from the ophthalmologist pop
into his inbox anywhere from 7 o’clock in
the morning to 10 at night.) What does keep Campochiaro
going is the scientific method. He gets really
excited when he talks about it. His trust in the
timeworn approach is so firm, in fact, that he
succeeds in making his own work sound almost pedestrian—as
though anyone following the same trail of biological
breadcrumbs would have arrived at the same results. “There’s
an observation that starts you down a particular
path,” he says modestly, “and one step
just leads to another.”

In truth, the succession of papers that make
up Campochiaro’s work on retinitis pigmentosa
might serve as a textbook case for how the scientific
method is supposed to proceed. His studies move
forward with a steady, deliberate progression,
with each new set of findings flowing logically
from the last.

Ideally, this pathway will lead to the development
of a treatment. And that’s what he is concentrating
on now. After proving that free radicals were indeed
chewing up the cone cells—or, more precisely,
destroying protein function and tricking those
cells into killing themselves—Campochiaro
started looking for a way to neutralize them. One
obvious option was to use antioxidants, molecules
that bind to the free radicals, rendering them
powerless before they can do any damage.

But this isn’t as simple as feeding laboratory
rats a few extra blueberries (the supermarket antioxidant
of choice, these days). Those free radicals act
quickly, latching on to other molecules almost
instantly. And it’s not entirely clear where
in the cell they’re doing most of their damage.
It could be in the cytoplasm. Or it may be that
they’re affecting mitochondria, the engine
of cells.

“If most of the damage is occurring in
mitochondria or just outside, it doesn’t
do much good for an antioxidant to be off in a
different part of the cell,” Campochiaro
says. “So in order for antioxidants to be
helpful, they have to be targeted at the right
place, at the right time, in the right concentration.
It’s a tall order.”

ALS researchers, he mentions, are facing the
same dilemma, and it’s proven to be especially
tricky. Back in 1993, neuroscientists demonstrated
a link between a genetic mutation and antioxidative
damage. The implication seemed fairly clear:
If ALS stemmed from a mutant protein that was causing
oxidative damage, then antioxidants should help.
Subsequent trials, however, with numerous antioxidant-based
treatments have proved inconclusive in fighting
the disease.

Campochiaro is further along the path in searching
for a treatment for RP. Recently, one of his outstanding
postdoctoral fellows, Keiichi Komeima, tested an
antioxidant cocktail in mice and found that it
did reduce cone-cell death and preserve retinal
function. In this methodical way, before moving
forward to testing the approach on RP patients,
Campochiaro is analyzing the results of a variety
of antioxidants given alone and in combination,
to see which ones are most effective.

“We’d like to try to maximize the
regimen,” he says, “so we can discover
the greatest effect we can achieve in the animal
models. If it’s sufficient, there would be
reason enough to test that regimen in clinical
trials on humans.”

There’s another possibility, too. The body
has built-in defense mechanisms against free radicals,
and it may be that finding a way to piggyback on
this system, or to strengthen it in some way, could
prove even more effective. “What we plan
to do,” Campochiaro says, “is to characterize
the antioxidant defense system in rods and cones,
figure out which are the most important components
and then determine if we can overexpress them or
increase their levels to see if we can decrease
cone cell death.”

Still, despite the steady progress of his research
so far and his well-developed plans for future
studies, Campochiaro acknowledges that finding
a treatment won’t be quick. What keeps him
focused is his dual role of clinician and scientist.

“When you’re working in a lab,” he
says, “you always have the sense that you’re
doing something worthwhile, but you sometimes lose
the forest for the trees.” To remind himself
of why he keeps staring at those slides in his
lab, why he works such long hours, puzzling over
the complex interactions of cellular molecules,
all he has to do is walk down one flight of stairs.